Sterilization of polymeric materials

ABSTRACT

A method of sterilizing a polymeric material that is sensitive to radiation. The method includes the steps of applying at least one radiosensitizer to the polymeric material and irradiating the polymeric material with a suitable radiation at an effective dose and time to sterilize the polymeric material. Also disclosed is a method of enhancing the ability of a medical device to withstand sterilization by radiation and a bioabsorbable polymeric medical device.

This application is a continuation of co-pending U.S. application Ser.No. 11/555,016, filed on Oct. 31, 2006, the entire contents of which arehereby incorporated by reference and for which priority is claimed under35 U.S.C. §120.

FIELD

This invention relates to polymers and, more particularly, to methodsfor the sterilization of radiosensitive polymeric materials for thereduction of active biological contaminants.

BACKGROUND

Medical devices designed for implantation are often composed ofmaterials that are gradually broken down by the body into products thatare excreted or metabolized. Devices produced from these bioabsorbablematerials tend to be more sensitive to certain physical and chemicaltreatments, including those necessary to sterilize medical devices. Inparticular, the mechanical integrity of medical devices produced frombioabsorbable polymers frequently suffers when sterilized usingconventional irradiation techniques.

Ionizing radiation treatments such as gamma-irradiation, electron beamirradiation, and x-ray irradiation generate free radicals and otheractivated molecules that damage the biological components ofcontaminating bacteria, fungi, and viruses and thus ensures theirinactivation. However, the constituent atoms of bioabsorbable materialsare also damaged by free radicals and activated molecules, which reducesthe structural integrity of the material.

Compounding the sterilization issue is the fact that steam sterilizationis incompatible with thermally or hydrolytically labile polymers.Ethylene oxide, a common and widely used sterilant, often reacts withsuch polymers, while also requiring prolonged periods of outgassing.

In view of these issues, many new medical advances cannot be implementedbecause the sterilization industry is unable to provide a suitablesterilant as part of the manufacturing process. As indicated above,medical devices, such as stents, sutures, catheters and endoscopes, arefabricated from, or coated with, sensitive polymers that cannot toleratesteam, irradiation, or ethylene oxide. Moreover, plasma sterilizationhas been shown to be incompatible with some medical equipment and leavestoxic residues.

Issues involving sterilization exist in other areas of medical treatmentas well, such as blood transfusions, blood factor replacement therapy,organ transplants and other forms of human therapy corrected or treatedby intravenous, intramuscular or other forms of injection orintroduction. Sterilization is also critical for the various biologicalmaterials that are prepared in media which contain various types ofplasma and/or plasma derivatives or other biologic materials and whichmay contain harmful prions, bacteria, viruses and other biologicalcontaminants or pathogens.

U.S. Pat. No. 5,362,442 proposes a method for sterilizing products toremove biological contaminants such as viruses, bacteria, yeasts, molds,mycoplasmas and parasites. The method proposed requires providing theproduct in a form that contains less than 20% solids and subsequentlyirradiating the product with gamma irradiation over an extended periodof time. The product is irradiated for a period of not less than 10hours. The extended irradiation time in conjunction with the low levelof solids in the product is said to substantially reduce the damage tothe product. The method is said to be useful in sterilizing sensitivematerials such as blood and blood components.

U.S. Pat. No. 6,187,572 proposes a method for inactivating viral and/orbacterial contamination in blood cellular matter, such as erythrocytesand platelets, or protein fractions. It is proposed that the cells orprotein fractions are mixed with chemical sensitizers, frozen orfreeze-dried, and irradiated with, for example, UV, visible, gamma orX-ray radiation while in the solid state.

U.S. Pat. No. 6,239,048 proposes a substrate such as a woven or nonwovenfabric bound with a light-activated dye alone or in combination withadditional conventional antimicrobial agents. The proposed substrate isimpregnated with a light-activated non-leachable dye said to haveantimicrobial and/or antiviral characteristics that can be imparted tothe substrate. Upon exposure to light, the dye is reported to generatesinglet oxygen that is said to kill microorganisms and viruses.

U.S. Pat. No. 6,908,591 proposes methods for sterilizing biologicalmaterials to reduce the level of one or more active biologicalcontaminants or pathogens, such as viruses, bacteria, yeasts, molds,fungi, prions or similar agents responsible, for TSEs and/or single ormulticellular parasites. The methods proposed involve the use offlavonoid/flavonol stabilizers in sterilizing biological materials withirradiation.

Despite these advances in the art, none of which address the issue ofsterilizing polymeric materials, there remains a need for methods ofsterilizing such materials that are effective for reducing the level ofactive biological contaminants or pathogens without an adverse effect onthe material.

SUMMARY

In one aspect, provided is a method of sterilizing a polymeric materialthat is sensitive to radiation, comprising the steps of applying atleast one radiosensitizer to the polymeric material and irradiating thepolymeric material with a suitable radiation at an effective dose andtime to sterilize the polymeric material.

In another aspect, provided is a polymeric medical device, comprising apolymeric composition in the form of a medical device, the medicaldevice having at least a first surface and at least one radiosensitizerapplied to the at least first surface of the medical device; wherein themedical device is effective for its intended use following sterilizationwith radiation.

In yet another aspect, provided is a method of making a polymericmedical device, comprising forming a medical device from a polymericcomposition, the medical device having at least a first surface andapplying at least one radiosensitizer to the at least first surface ofthe polymeric medical device; wherein the medical device is effectivefor its intended use following sterilization with radiation.

In still yet another aspect, provided is a method of producing aarticle, comprising providing a polymer composition, heating the polymerto a melt processing temperature, forming an article from the polymercomposition using a melt processing apparatus, the article having atleast a first surface and applying at least one radiosensitizer to theat least first surface of the article, wherein the article is effectivefor its intended use following sterilization with radiation.

In a further aspect, provided is a method of enhancing the ability of amedical device to withstand sterilization by radiation, comprising thestep of applying at least one radiosensitizer to the medical device,wherein the article is effective for its intended use followingsterilization with radiation.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in more detail with reference to theforms herein disclosed, given only by way of example, and with referenceto the accompanying drawings, in which:

FIG. 1 presents plots of cfu recovered as a function of irradiation dosefor the data of Table 2;

FIG. 2 presents plots of log change vs. inoculum as a function ofirradiation dose for the data of Table 2;

FIG. 3 presents plots of cfu recovered as a function of irradiation dosefor the data of Tables 3 and 4;

FIG. 4 presents plots of cfu recovered as a function of irradiation dosefor the Spongostan® gelatin samples treated with 50 μg/ml methylene blueor with 2.5 mg/ml of riboflavin or left untreated as a control; and

FIG. 5 presents a summary of the log change vs. untreated control as afunction of irradiation dose for the data of Examples 1 through 4.

DETAILED DESCRIPTION

Definitions

Unless defined otherwise, all technical and scientific terms used hereinare intended to have the same meaning as is commonly understood by oneof ordinary skill in the relevant art.

As used herein, the singular forms “a,” “an,” and “the” include theplural reference unless the context clearly dictates otherwise.

As used herein, the term “sterilize” is intended to mean a reduction inthe level of at least one active or potentially active biologicalcontaminant or pathogen found on the radiosensitive bioabsorbablematerials being treated in accordance herewith.

As used herein, the term “biological contaminant or pathogen” isintended to mean a contaminant or pathogen that, upon direct or indirectcontact with a radiosensitive polymeric material, may have a deleteriouseffect upon a recipient thereof. As used herein, the term “activebiological contaminant or pathogen” is intended to mean a biologicalcontaminant or pathogen that is capable of causing a deleterious effect,either alone or in combination with another factor, such as a secondbiological contaminant or pathogen or a native protein or antibody, upona recipient of the radiosensitive polymeric material.

As used herein, the term “radiosensitizer” is intended to mean asubstance that selectively targets biological contaminants or pathogens,including the various viruses, bacteria (including inter- andintracellular bacteria, such as mycoplasmas, ureaplasmas, nanobacteria,chlamydia, rickettsias), yeasts and molds, rendering them more sensitiveto inactivation by radiation, therefore permitting the use of a lowerdose of radiation than in the absence of the sensitizer.

As used herein, the term “radiation” is intended to mean radiation ofsufficient energy to sterilize at least some component of the irradiatedpolymeric material. Types of radiation include, but are not limited to,the following: (i) corpuscular (streams of subatomic particles such asneutrons, electrons, and/or protons); (ii) electromagnetic (originatingin a varying electromagnetic field, such as radio waves, visible (bothmono and polychromatic) and invisible light, infrared, ultravioletradiation, x-radiation, and gamma rays and mixtures thereof); and (iii)sound and pressure waves. Such radiation is often described as eitherionizing (capable of producing ions in irradiated materials) radiation,such as gamma rays, and non-ionizing radiation, such as visible light.The sources of such radiation may vary and, in general, the selection ofa specific source of radiation is not critical provided that sufficientradiation is given in an appropriate time and at an appropriate dose toeffect sterilization. In practice, gamma radiation is usually producedby isotopes of Cobalt or Cesium, while UV and X-rays are produced bymachines that emit UV and X-radiation, respectively, and electrons areoften used to sterilize materials in a method known as “E-beam”irradiation that involves their production via a machine. Visible light,both mono- and polychromatic, is produced by machines and may, inpractice, be combined with invisible light, such as infrared and UV,that is produced by the same machine or a different machine.

As indicated above, many implanted medical devices are composed ofmaterials that are gradually broken down by the body into products thatare excreted or metabolized. Consequently, these “bioabsorbablematerials” are more sensitive to the certain physical and chemicaltreatments, particularly those necessary to sterilize medical devices.This is especially true of exposure of these materials to ionizingradiation such as gamma-irradiation, electron beam irradiation, andx-ray irradiation. Such treatments generate free radicals and otheractivated molecules that damage the biological components ofcontaminating bacteria, fungi, and viruses and thus ensures theirinactivation. The constituent atoms of bioabsorbable materials are alsodamaged by free radicals and activated molecules, which reduces thestructural integrity of the material.

In one form, a sterilization method that reduces the effective dose ofionizing radiation needed for disinfection of a polymeric material to alevel where the structural properties of the material are notsignificantly affected is disclosed. The method includes the steps ofapplying at least one radiosensitizer to a polymeric material andirradiating the polymeric material with a suitable radiation at aneffective dose to sterilize said polymeric material. The combination ofthe radiosensitizer with low dose irradiation has been found to enablethe effective sterilization of medical devices containing radiosensitivematerials.

In another form, provided is a polymeric medical device, comprising: apolymeric composition in the form of a medical device, the medicaldevice having at least a first surface; at least one radiosensitizerapplied to the at least first surface of the medical device; wherein themedical device is effective for its intended use following sterilizationwith radiation.

In yet another form, provided is a method of making a polymeric medicaldevice, comprising: forming a medical device from a polymericcomposition, the medical device having at least a first surface; andapplying at least one radiosensitizer to the at least first surface ofthe polymeric medical device; wherein the medical device is effectivefor its intended use following sterilization with radiation.

In still yet another form, provided is a method of producing a polymericarticle, comprising: providing a polymer composition; heating thepolymer to a melt processing temperature; forming an article from thepolymer composition using a melt processing apparatus, the articlehaving at least a first surface; and applying at least oneradiosensitizer to the at least first surface of the polymeric article;wherein the polymeric article is effective for its intended usefollowing sterilization with radiation.

In a further form, provided is a method of enhancing the ability of apolymeric medical device to withstand sterilization by radiation,comprising the step of applying at least one radiosensitizer to thepolymeric medical device, wherein the polymeric article is effective forits intended use following sterilization with radiation.

Suitable radiosensitizers include numerous compounds familiar to thoseskilled in the art including, but not limited to, psoralen and itsderivatives and analogs (including 3-carboethoxy psoralens); inactinesand their derivatives and analogs; angelicins, khellins and coumarinswhich contain a halogen substituent and a water solubilization moiety,such as quaternary ammonium ion or phosphonium ion; nucleic acid bindingcompounds; brominated hematoporphyrin; phthalocyanines; purpurins;porphyrins; halogenated or metal atom-substituted derivatives ofdihematoporphyrin esters, hematoporphyrin derivatives, benzoporphyrinderivatives, hydrodibenzoporphyrin dimaleimade, hydrodibenzoporphyrin,dicyano disulfone, tetracarbethoxy hydrodibenzoporphyrin, andtetracarbethoxy hydrodibenzoporphyrin dipropionamide; doxorubicin anddaunomycin, which may be modified with halogens or metal atoms;netropsin; BD peptide, S2 peptide; S-303 (ALE compound); dyes, such ashypericin, methylene blue, eosin, fluoresceins (and their derivatives),flavins, merocyanine 540; photoactive compounds, such as bergapten; andSE peptide. As may be appreciated, derivatives of these compounds,particularly halogenated (brominated) entities, can also be used. In oneform, incorporation of riboflavin into the coating of the polymericmaterial polygalactin 910 is contemplated. As may be appreciated bythose skilled in the art, polygalactin 910 is used to produce Vicryl®suture material. When methylene blue is selected as the radiosensitizer,an effective amount to be employed will range from about 20 μg/mL toabout 75 μg/mL (about 20 ppm to about 75 ppm). When riboflavin isselected as the radiosensitizer, an effective amount to be employed willrange from about 200 μg/mL to about 5 mg/mL (about 200 ppm to about 5ppt).

At least one radiosensitizer may be introduced into a polymeric materialaccording to any of the methods and techniques known and available toone skilled in the art, including, for example, but not by way oflimitation, soaking the polymeric material in a solution containing theradiosensitizer(s) at atmospheric pressure and room temperature.Alternatively, the at least one radiosensitizer may be introduced bysoaking the polymeric material in a solution containing theradiosensitizer(s) under pressure, at elevated temperature, and/or inthe presence of a penetration enhancer, such as dimethylsulfoxide.

Other methods of introducing at least one radiosensitizer into apolymeric material include, but are not limited to, the following:applying a gas containing the radiosensitizer(s), under pressure and/orat elevated temperature; injecting the radiosensitizer(s) or a solutioncontaining the radiosensitizer(s) directly into the polymeric material;placing the polymeric material under reduced pressure and thenintroducing a gas or solution containing the radiosensitizer(s);dehydrating the polymeric material, such as by using a buffer of highionic and/or osmolar strength, and rehydrating the polymeric materialwith a solution containing the radiosensitizer(s); applying a high ionicstrength solvent containing the radiosensitizer(s), which may optionallybe followed by a controlled reduction in the ionic strength of thesolvent; cycling the polymeric material between solutions of high ionicand/or osmolar strength and solutions of low ionic and/or osmolarstrength containing the radiosensitizer(s); applying the at least oneradiosensitizer within or as a component of a microemulsion; andcombinations of two or more of these methods.

The mechanism of action of many of these compounds involves its bindingto the nucleic acid (DNA/RNA) of the contaminating microbe. Uponirradiation, the compound absorbs the energy and locally causes damageto the nucleic acid, thereby preventing replication of themicroorganism. Since the polymeric materials do not contain nucleicacid, little damage is caused by the radiosensitizer after irradiation.Advantageously, since many of the radiosensitizers are considered safefor blood product sterilization, their safety/toxicity profile isgenerally favorable and they can remain on a medical device with littlerisk to the patient.

The method disclosed herein is effective against such biologicalcontaminants or pathogens, including the various viruses, bacteria(including inter- and intracellular bacteria, such as mycoplasmas,ureaplasmas, nanobacteria, chlamydia, rickettsias), yeasts and molds.

The radiation employed in the methods disclosed herein may be anyradiation effective for the sterilization of the polymeric materialbeing treated. The radiation may be corpuscular, including acceleratedelectron irradiation (E-beam) radiation. The radiation may beelectromagnetic radiation, including x-rays, infrared, visible light, UVlight and mixtures of various wavelengths of electromagnetic radiation.The radiation may be gamma radiation from a cobalt or other isotopicsource or irradiation with X-rays.

According to the methods disclosed herein, the polymeric material isirradiated with the radiation at a dose effective for the sterilizationof the polymeric material, while not producing an unacceptable level ofdamage to that material. Suitable doses of irradiation may varydepending upon the nature and characteristics of the particularpolymeric material being irradiated, the particular form of radiationinvolved and/or the particular biological contaminants or pathogensbeing inactivated. Suitable doses of irradiation can be determinedempirically by one skilled in the art. The dose of irradiation may beconstant for the duration of the sterilization procedure. When this isimpractical or otherwise not desired, a variable or discontinuousirradiation may be utilized.

According to the methods disclosed herein, the dose of irradiation maybe optimized to produce the most advantageous combination of productrecovery and time required to complete the operation. Advantageously,low (<3 kGy) doses may be utilized in the methods described herein toachieve such results. The dose of irradiation is selected to minimizestructural damage to the polymeric material while still sterilizing thepolymeric material.

According to one form, the dose of irradiation is not more than about5.0 kGy, or between about 0.1 kGy and 3.0 kGy, or between about 0.1 kGyand 1.0 kGy, or between about 0.1 kGy and 0.5 kGy, or between about 0.1kGy and 0.3 kGy.

According to the methods disclosed herein, the polymeric material to besterilized is irradiated with a dose effective for the sterilization ofthe polymeric material. Suitable irradiation doses may vary dependingupon the particular form of radiation involved and/or the nature andcharacteristics of the particular polymeric material being irradiated.As may be appreciated, suitable irradiation doses can be determinedempirically by one skilled in the art.

In certain forms disclosed herein, when the polymeric material to betreated contains an aqueous or non-aqueous solvent, or a mixture of suchsolvents, at least one stabilizer is introduced according to any of themethods and techniques known and available to one skilled in the art,including soaking the polymeric material in a solution containing thestabilizer(s), preferably under pressure, at elevated temperature and/orin the presence of a penetration enhancer, such as dimethylsulfoxide,and more preferably, when the stabilizer(s) is a protein, at a highconcentration. Other methods of introducing at least one stabilizer intoa polymeric material include, but are not limited to, the following:applying a gas containing the stabilizer(s), preferably under pressureand/or at elevated temperature; injecting the stabilizer(s) or asolution containing the stabilizer(s) directly into the polymericmaterial; placing the polymeric material under reduced pressure and thenintroducing a gas or solution containing the stabilizer(s); dehydratingthe polymeric material, such as by using a buffer of high ionic and/orosmolar strength, and rehydrating the polymeric material with a solutioncontaining the stabilizer(s); applying a high ionic strength solventcontaining the stabilizer(s), which may optionally be followed by acontrolled reduction in the ionic strength of the solvent; cycling thepolymeric material between solutions of high ionic and/or osmolarstrength and solutions of low ionic and/or osmolar strength containingthe stabilizer(s); applying the at least one stabilizer within or as acomponent of a microemulsion; and combinations of two or more of thesemethods.

In certain forms disclosed herein, at least one cryopreservative isintroduced into a polymeric material according to any of the methods andtechniques known and available to one skilled in the art, includingsoaking the polymeric material in a solution containing thecryopreservative(s), preferably under pressure, at elevated temperatureand/or in the presence of a penetration enhancer, such asdimethylsulfoxide. Other methods of introducing at least onecryopreservative into a polymeric material include, but are not limitedto, the following: applying a gas containing the cryopreservative(s),under pressure and/or at elevated temperature; injecting thecryopreservative(s) or a solution containing the cryopreservative(s)directly into the polymeric material; placing the polymeric materialunder reduced pressure and then introducing a gas or solution containingthe cryopreservative(s); dehydrating the polymeric material, such as byusing a buffer of high ionic and/or osmolar strength, and rehydratingthe polymeric material with a solution containing thecryopreservative(s); applying a high ionic strength solvent containingthe cryopreservative(s), which may optionally be followed by acontrolled reduction in the ionic strength of the solvent; cycling thepolymeric material between solutions of high ionic and/or osmolarstrength and solutions of low ionic and/or osmolar strength containingthe cryopreservative(s); applying the at least one cryopreservativewithin or as a component of a microemulsion; and combinations of two ormore of these methods.

According to certain forms disclosed herein, the polymeric material maybe subjected to a treatment effective to enhance penetration of the oneor more stabilizers and/or cryopreservatives and/or sensitizers into thepolymeric material. Such treatments include physical treatments andchemical treatments.

For instance, with respect to chemical treatment, the polymeric materialmay be treated with one or more compounds that cause an increase in thedistance between molecules in the polymeric material, thereby promotingpenetration of the stabilizers and/or cryopreservatives and/orsensitizers into the polymeric material. Alternatively, the chemicaltreatment may include treating the polymeric material with amicroemulsion effective to enhance penetration of the stabilizers and/orcryopreservatives and/or sensitizers into the polymeric material.

Similarly, the polymeric material may be treated with one or morecompounds that cause macromolecules in the polymeric material to becomeless compact, or relaxed, thereby promoting penetration of thestabilizer(s) and/or cryopreservatives and/or sensitizer(s) into thepolymeric material or providing a greater surface area of polymericmaterial to be in contact with the stabilizer(s) and/orcryopreservatives and/or sensitizer(s). The compounds that causemacromolecules in the polymeric material to become less compact, orrelaxed, may also be applied prior to introduction of the stabilizer(s)and/or cryopreservatives and/or sensitizer(s), which may then beintroduced in a similar solution followed by application of a solutioncontaining a similar amount of stabilizer(s) and/or cryopreservativesand/or sensitizer(s) but a reduced amount of the compounds that causemacromolecules in the polymeric material to become less compact, orrelaxed. Repeated applications of such solutions, with progressivelylower amounts of compounds that cause macromolecules in the polymericmaterial to become less compact, or relaxed, may subsequently heapplied.

The compounds that promote penetration may be used alone or incombination, such as a combination of a compound that causesmacromolecules in the polymeric material to become less compact and acompound that causes an increase in the distance between molecules inthe polymeric material.

Further, in those forms wherein the stabilizer(s) and/orcryopreservatives and/or sensitizer(s) is cationic, one or more anioniccompounds may be added to the solution containing the stabilizer(s)and/or cryopreservatives and/or sensitizer(s) prior to and/or duringapplication thereof to the polymeric material. The anionic compound(s)may also be applied prior to introduction of the stabilizer(s) and/orcryopreservatives and/or sensitizer(s), which may then be introduced ina similar solution followed by application of a solution containing asimilar amount of stabilizer(s) and/or cryopreservatives and/orsensitizer(s) but a reduced amount of the anionic compound(s). Repeatedapplications of such solutions, with progressively lower amounts ofanionic compound(s) may subsequently be applied.

Similarly, in those forms wherein the stabilizer(s) and/orcryopreservatives and/or sensitizer(s) are anionic, one or more cationiccompounds may be added to the solution containing the stabilizer(s)and/or cryopreservatives and/or sensitizer(s) prior to and/or duringapplication thereof to the polymeric material. The cationic compound(s)may also be applied prior to introduction of the stabilizer(s) and/orcryopreservatives and/or sensitizer(s), which may then be introduced ina similar solution followed by application of a solution containing asimilar amount of stabilizer(s) and/or cryopreservatives and/orsensitizer(s) but a reduced amount of the cationic compound(s). Repeatedapplications of such solutions, with progressively lower amounts ofcationic compound(s) may subsequently be applied.

Regarding physical treatments effective to enhance penetration of theone or more stabilizer(s) and/or cryopreservative(s) and/orsensitizer(s) into the polymeric material, examples include, but are notlimited to, physical agitation, such as by shaking or sonication.

According to the forms employing physical agitation, such as sonicationor shaking, physical agitation is carried out for a time effective toenhance penetration of the one or more stabilizer(s) and/orcryopreservative(s) and/or sensitizer(s) into the polymeric material.The duration of such treatment will depend upon, among other factors,the nature of the one or more polymeric material, the nature of thesolvent(s) employed, and the nature of the one or more stabilizer(s)and/or cryopreservative(s) and/or sensitizer(s). Suitable times mayeasily be determined empirically by one having ordinary skill in theart.

Polymers contemplated for use in the medical devices and articlesdisclosed herein include, but are not limited to, bioabsorbable polymerssuch as poly(lactide), including L (−), D (+), meso and racemic lactideform, poly(glycolide), poly(dioxanone), poly(ε-caprolactone),poly(hydroxybutyrate), poly(β-hydroxybutyrate), poly(hydroxyvalerate),poly(tetramethyl carbonate), and poly(amino acids) and copolymers andterpolymers thereof. Also contemplated herein is a copolymer blendcomprising poly(lactide)-co-poly(glycolide) in a 50/50 wt. % ratiohaving a first copolymer of a weight average molecular weight betweenabout 40,000 to about 100,000 Daltons, and a second copolymer of aweight average molecular weight between about 5,000 to about 30,000Daltons.

As indicated above, contemplated for use herein is polylactic acid (PLAor poly(lactide)), which is prepared from the cyclic diester of lacticacid (lactide) by ring opening polymerization. As may be appreciated,lactic acid exists as two optical isomers or enantiomers. TheL-enantiomer occurs in nature, a D, L racemic mixture results from thesynthetic preparation of lactic acid. Fibers spun from “L” poly(lactide)(mp. 170 C) have high crystallinity, when drawn, whereas fibers spunfrom poly DL-lactide are amorphous. Crystalline poly-L-lactide is moreresistant to hydrolytic degradation than the amorphous DL form.

High molecular weight PLA polymer can be readily prepared, with fibersamples having high tensile strength commercially available and producedby hot-drawing filaments spun from solution. Exposure of polylactic acidto gamma radiation has been shown to result in a decrease in molecularweight.

Unlike PLA, which is absorbed slowly, PGA is absorbed within a fewmonths post-implantation, due to greater hydrolytic susceptibility. Invitro experiments have shown an effect on degradation by enzymes,buffer, pH, annealing treatments, and gamma irradiation. Acceleration ofin vivo degradation due to gamma irradiation has been exploited tocreate devices where early fragmentation is desired. Polyglycolic acid(PGA or poly(glycolide)) is a totally synthetic absorbable polymercontemplated for use herein.

Also contemplated for use herein are copolymers of PGA and PLA, namelypoly(lactide-co-glycolide). The copolymers are amorphous between thecompositional range 25 to 70 mole percent glycolide. Pure polyglycolideis about 50% crystalline, whereas pure poly-L-lactide is reported to beabout 37% crystalline. Like pure PGA and pure PLA, a 90/10 PGA/PLA isalso weakened by gamma irradiation. Another approach to copolymerizationincludes using a starting monomer that is neither lactide nor glycolide,but rather an unsymmetrical cyclic diester containing one lactate andone glycolate moiety. This monomer produces a polymer with the sameempirical formula as poly(lactide-co-50%-glycolide), but possessesdifferent properties due to a more stereoregular configuration.

Another polymer contemplated for use herein is polydioxanone. Themonomer p-dioxanone, is analogous to glycolide but yields apoly-(ether-ester). Poly(dioxanone) monofilament fibers are known toretain tensile strength longer than braided polyglycolide and areabsorbed within about six months with minimal tissue response.Poly(dioxanone) degradation in vitro is affected by gamma irradiationdosage, but not substantially by the presence of enzymes.

Also contemplated for use herein is the polymer poly(ε-caprolactone).Poly(ε-caprolactone) is synthesized from ε-caprolactone. Additionally,copolymers of ε-caprolactone and L-lactide are contemplated for useherein. They are known to be elastomeric when prepared from 25%ε-caprolactone, 75% L-lactide and rigid when prepared from 10%ε-caprolactone, 90% L-lactide.

Also contemplated for use herein are the bioabsorbable polymerspoly(hydroxybutyrate) and poly(hydroxyvalerate). Poly(β-hydroxybutyrate)(PHB) is a biodegradable polymer that occurs both in nature and caneasily be synthesized in vitro. Synthetic PHB, however, has not shownthe stereoregularity found in the natural product. High MW, crystalline,and optically active PHB have been extracted from bacteria. PHB polymeris melt processable and has been proposed for use as absorbable suture.Recent improvements in the extraction process have resulted in renewedinterest in PHB for both medical and nonmedical applications. Copolymersof hydroxybutyrate and hydroxyvalerate have been developed to provide awide variety of mechanical properties and more rapid degradation thancan be achieved with pure PHB, and are also contemplated for use herein.

Also potentially benefiting from the methods disclosed herein is theclass of absorbable polymers known as poly(amino acids). The use ofamino acids as building blocks for synthetic absorbable polymers hasmade great strides.

Also contemplated for use herein are the bioabsorbable polymerscategorized as proteinaceous polymers. Such polymers include, withoutlimitation, alginate albumins, algal proteins, apoproteins, lectins,lipoproteins, metalloproteins, polyproteins, collagen, elastin,fibronectins, laminin, tenascin, vitronectin, fibroin, gelatin, keratin,reticulin, poly(alpha-amino acid), poly(beta-amino acid),poly(gamma-amino acid), polyimino acid, polypeptide and derivatives ofany of the above. As will be shown in more detail below, theproteinaceous polymer may comprise gelatin.

Also contemplated for use herein are nonabsorbable polymers, including,but not limited to, polyolefins, polycarbonates, polyvinylchlorides,styrenes, including acrylonitrile butadiene styrenes, nylons, acrylics,thermoplastic urethanes, thermoplastic elastomers, thermoset plastics,polyamides, polyesters and polyethylene terephthalate. Examples ofpolyolefins for use herein include, but are not limited to alpha-olefinsproduced by Ziegler-Natta or metallocene catalysts, such aspolyethylene, polypropylene, copolymers and terpolymers thereof.

Medical devices produced in accordance herewith are not believed tosuffer physical or mechanical damage during sterilization, when suchsterilization is conducted in accordance with the methods disclosedherein. In production of the medical devices disclosed herein, theradiosensitizers could be coated onto the medical device or packagingmaterial, injected into a package, or delivered in some other mannerprior to irradiation. The medical devices contemplated herein includethose selected from the group consisting of sutures, clips, staples,pins, screws, fibers, films, stents, gelcaps, tablets, microspheres andinjectable polymer solutions.

Specific embodiments of the present invention will now be describedfurther, by way of example. While the following examples demonstratecertain embodiments of the invention, they are not to be interpreted aslimiting the scope of the invention, but rather as contributing to acomplete description of the invention.

EXAMPLES Example 1 Radiosensitization of Bacteria Coated Onto a MaterialSurface

Enterococcus faecalis ATCC 29212, grown overnight in tryptic soy brothat 37° C. without shaking, were centrifuged and resuspended in 2%glucose at a concentration of about 5×10⁷ cfu/ml. The radiosensitizercompounds listed below, riboflavin, methylene blue, ascorbic acid,sodium nitrate, and toluidine blue, were added to the bacteria at theconcentrations indicated, then incubated for 2 hours at room temperaturewith shaking. The cfu contained in each sample were quantified bydilution plating and the values are listed as “post-treatment cfuadded.” None of the radiosensitizer treatments alone appeared to have asignificant adverse effect on the bacteria.

Following radiosensitizer treatment, 0.05 ml of each mixture (containingapproximately 1×10⁶ cfu) was spotted onto sterile 12 mm paper disks andthe disks air dried for 30 minutes. The disks were then placed insterile tubes and left untreated or irradiated with 0.3 kGy. The cfuwere recovered from the disks by vortexing with glass beads for 1 minutein 0.85% saline with 0.35 g/l lecithin and 2.5 ml/l Tween 80.Quantification of the cfu was then performed by dilution plating ontotryptic soy agar.

Compared to the non-irradiated samples, the percentage of cfu recoveredfrom the irradiated radiosensitizer-treated samples was lower that thatof the untreated control. Thus, the radiosensitizer treatment enhancedthe killing efficiency of the irradiation, with methylene blue, ascorbicacid, toluidine blue and sodium nitrate having the greatest effect.

TABLE 1 Post- Conc. Treatment Percent (μg/ml) CFU Survival Treatment mlAdded 0 kGy 0.3 kGy 0.3 vs. 0 kGy Control 9.00E+05 990 51 5.15Riboflavin 200 8.50E+05 1080 3 0.28 1000 8.00E+05 1080 9 0.83 Methylene20 7.80E+05 2250 3 0.13 Blue Ascorbic Acid 200 8.55E+05 3270 9 0.28Sodium Nitrate 5000 8.15E+05 420 0 0.00 Toluidine Blue 20 7.70E+05 87 00.00 100 4.65E+05 72 0 0.00

Example 2 Radiosensitization of Bacteria Coated onto a Medical DeviceComprised of Synthetic Polymer

Enterococcus faecalis ATCC 29212, grown overnight in tryptic soy brothat 37° C. without shaking, were centrifuged and resuspended in phosphatebuffered saline (PBS) at a concentration of roughly 2×10⁹ cfu/ml. Thebacteria were then incubated for 2 hours at room temperature with orwithout 50 μg/ml methylene blue. The cfu contained in each sample afterthis incubation were quantified by dilution plating. The untreatedsample contained 1.8×10⁹ cfu/ml and the sample treated with methyleneblue contained 1.6×10⁹ cfu/ml, indicating that incubation with methyleneblue did not significantly affect the bacterial number.

Following radiosensitizer treatment, 0.01 ml of each mixture (containingapproximately 2×10⁷ cfu) was spotted onto nine 1 cm×1 cm squares ofVicryl® mesh that were then air dried for 60 minutes. Triplicate sampleswere then placed in sterile tubes and left untreated or irradiated with0.1 or 0.2 kGy. The cfu were recovered from the meshes by vortexing withglass beads for 1 minute in 0.85% saline with 0.35 g/l lecithin and 2.5ml/l Tween 80. Quantification of the cfu was then performed by dilutionplating onto tryptic soy agar.

TABLE 2 Plated Total CFU Avg CFU Std Log Total Avg Log Std Dev kGyInoculum CFU Rec Rec Dev CFU CFU Log Control 0 1.80E+07 8.80E+054.40E+06 2.70E+06 1.68E+06 6.64 6.36 0.32 5.30E+05 2.65E+06 6.422.10E+05 1.05E+06 6.02 0.1 6.10E+04 3.05E+05 3.85E+05 7.09E+04 5.48 5.580.08 8.80E+04 4.40E+05 5.641 8.20E+04 4.10E+05 5.61 0.2 1.05E+045.25E+04 8.00E+04 4.05E+04 4.72 4.87 0.20 2.53E+04 1.27E+05 5.101.22E+04 6.10E+04 4.79 50 μg/l MB 0 1.60E+07 2.33E+05 1.17E+06 7.40E+055.38E+05 6.07 5.72 0.51 1.84E+05 9.20E+05 5.96 2.70E+04 1.35E+05 5.130.1 7.60E+02 3.80E+03 1.04E+04 9.28E+03 3.58 3.90 0.38 4.20E+03 2.10E+044.32 1.27E+03 6.35E+03 3.80 0.2 5.20E+02 2.60E+03 1.83E+03 1.37E+03 3.413.08 0.59 5.30E+02 2.65E+03 3.42 5.00E+01 2.50E+02 2.40

FIG. 1 presents plots of cfu recovered as a function of irradiation dosefor the data of Table 2. FIG. 2 presents plots of log change vs.inoculum as a function of irradiation dose for the data of Table 2. Asmay be seen, a 15% recovery from the control, unirradiated sample wasobserved. A 4.6% recovery from the methylene blue-treated, unirradiatedsample was observed. Also, it may be noted that methylene blue had asmall effect on bacterial recovery in this experiment. A 0.1 kGy dosecaused a 0.8-log reduction in the untreated control, while a 0.2 kGydose caused a 1.5-log reduction in the untreated control. Thecombination of methylene blue and a 0.1 dose or a 0.2 kGy dose caused a3 to 4 log reduction in cfu recovered.

Example 3 Radiosensitization of Bacteria Coated onto a Medical DeviceComprised of Prolene® and Vicryl® Synthetic Polymers

Enterococcus faecalis ATCC 29212, grown overnight in tryptic soy brothat 37° C. without shaking, were centrifuged and resuspended in phosphatebuffered saline (PBS) at a concentration of about 5×10⁸ cfu/ml. Thebacteria were then incubated for 2 hours at room temperature with orwithout 50 μg/ml methylene blue. The cfu contained in each sample afterthis incubation were quantified by dilution plating. The untreatedsample contained 4.8×10⁸ cfu/ml and the sample treated with methyleneblue contained 4.2×10⁸ cfu/ml, indicating that incubation with methyleneblue did not significantly affect the bacterial number.

Following radiosensitizer treatment, 0.01 ml of each mixture (containingapproximately 5×10⁸ cfu) was spotted onto nine 1 cm×1 cm squares ofProlene® mesh that were then air dried for 60 minutes. Triplicatesamples were then placed in sterile tubes and left untreated orirradiated with 0.1 or 0.3 kGy. The cfu were recovered from the mesh byvortexing with glass beads for 1 minute in 0.85% saline with 0.35 g/llecithin and 2.5 ml/l Tween 80. Quantification of the cfu was thenperformed by dilution plating onto tryptic soy agar.

TABLE 3 Test Results for Prolene ® Samples Plated Total CFU Avg CFU StdLog Red v Log Red Log Red v kGy Inoculum CFU Recovered Recovered DevInoculum v 0 kGy Control Control 0.0 4.80E+06 4.60E+04 1.15E+05 8.33E+043.25E+04 −1.8 0.0 0.0 2.00E+04 5.00E+04 3.40E+04 8.50E+04 0.3 4.00E+001.00E+01 1.50E+01 4.33E+00 −5.5 −3.7 0.0 7.00E+00 1.75E+01 7.00E+001.75E+01 50 μg/ml 0.0 4.20E+06 5.90E+02 1.48E+03 2.38E+03 1.49E+03 −3.20.0 −1.5 MethyleneBlue 6.20E+02 1.55E+03 1.64E+02 4.10E+03 0.3 0.00E+000.00E+00 0.00E+00 0.00E+00 −6.6 −3.4 −1.2 0.00E+00 0.00E+00 0.00E+000.00E+00

Following radiosensitizer treatment, 0.01 ml of each mixture (containingapproximately 5×10⁸ cfu) was spotted onto nine 1 cm×1 cm squares ofVicryl® mesh that were then air dried for 60 minutes. Triplicate sampleswere then placed in sterile tubes and left untreated or irradiated with0.1 or 0.3 kGy. The cfu were recovered from the mesh by vortexing withglass beads for 1 minute in 0.85% saline with 0.35 g/l lecithin and 2.5ml/l Tween 80. Quantification of the cfu was then performed by dilutionplating onto tryptic soy agar.

TABLE 4 Test Results for Vicryl ® Samples Plated Total CFU Avg CFU StdLog Red v Log Red Log Red v kGy Inoculum CFU Recovered Recovered DevInoculum v 0 kGy Control Control 0.0 4.80E+06 1.60E+04 4.00E+04 2.63E+052.30E+05 −1.3 0.0 0.0 2.00E+05 5.00E+05 1.00E+05 2.50E+05 0.3 7.00E+021.75E+03 6.60E+02 9.49E+02 −3.9 −2.6 0.0 8.00E+00 2.00E+01 8.40E+012.10E+02 50 μg/ml 0.0 4.20E+06 3.80E+03 9.50E+03 1.79E+04 8.14E+03 −2.40.0 −1.2 MethyleneBlue 7.40E+03 1.85E+04 1.03E+02 2.58E+04 0.3 6.30E+011.58E+02 9.83E+01 8.57E+01 −4.6 −2.3 −0.8 5.50E+01 1.38E+02 0.00E+000.00E+00

FIG. 3 presents plots of cfu recovered as a function of irradiation dosefor the data of Tables 3 and 4. As may be seen, the combination ofmethylene blue and irradiation significantly reduced the number ofbacteria recovered from the Prolene® and Vicryl® mesh samples comparedto methylene blue or irradiation alone. Methylene blue and gammairradiation appear to act in a synergistic fashion to eliminate bacteriafrom the surface of the medical device, i.e. methylene blue enhanced theeffect of irradiation in sterilization of the device.

Example 4 Radiosensitization of Bacteria Coated onto a Medical DeviceComprised of Spongostan® Gelatin Sponge

Enterococcus faecalis ATCC 29212, grown overnight in tryptic soy brothat 37° C. without shaking, were centrifuged and resuspended in phosphatebuffered saline (PBS) at a concentration of about 5×10⁸ cfu/ml. Thebacteria were then incubated for 2 hours at room temperature with 50μg/ml methylene blue or with 2.5 mg/ml of riboflavin or without anyfurther treatment. The cfu contained in each sample after thisincubation were quantified by dilution plating. The untreated samplecontained 4.8×10⁸ cfu/ml, the sample treated with methylene bluecontained 4.2×10⁸ cfu/ml, indicating that incubation with methylene bluedid not significantly affect the bacterial number and the sample treatedwith riboflavin also contained 4.2×10⁸ cfu/ml, again indicating thatincubation with riboflavin did not significantly affect the bacterialnumber

Following radiosensitizer treatment, 0.01 ml of each mixture (containingapproximately 5×10⁸ cfu) was spotted onto nine 1 cm×1 cm squares ofSpongostan® gelatin sponge that were then air dried for 60 minutes.(Spongostan® is a dry artificial sponge of fibrin prepared by clottingwith thrombin, a foam or solution of fibrinogen. It is used inconjunction with thrombin as a hemostatic in surgery at sites wherebleeding cannot be controlled by more common methods.) Triplicatesamples were then placed in sterile tubes and left untreated orirradiated with 0.1 or 0.3 kGy. The cfu were recovered from the spongeby vortexing with glass beads for 1 minute in 0.85% saline with 0.35 g/llecithin and 2.5 ml/l Tween 80. Quantification of the cfu was thenperformed by dilution plating onto tryptic soy agar.

FIG. 4 presents plots of cfu recovered as a function of irradiation dosefor the Spongostan® gelatin samples treated with 50 μg/ml methylene blueor with 2.5 mg/ml of riboflavin or left untreated as controls. FIG. 5presents a summary of the log change vs. untreated control as a functionof irradiation dose for the data of Examples 1 through 4.

As demonstrated hereinabove, the use of a radiosensitizer has been foundto significantly reduce the dose of radiation used for disinfection,thereby ensuring that the structural features of the polymeric materialare not significantly affected. The method disclosed herein provides adistinct advantage over currently used sterilization methods, such asethylene oxide treatments, by reducing the cost, environmental impact,and processing time of sterilization of medical devices containingpolymeric materials.

While the subject invention has been illustrated and described in detailin the drawings and foregoing description, the disclosed embodiments areillustrative and not restrictive in character. All changes andmodifications that come within the scope of the invention are desired tobe protected.

What is claimed is:
 1. A method of making a polymeric medical device,comprising: (a) providing a bioabsorbable polymer composition; (b)heating the polymer to a melt processing temperature; (c) forming saidmedical device from the polymer composition using a melt processingapparatus, the medical device having at least a first surface; (d)applying at least one radiosensitizer to the at least first surface ofthe polymeric medical device; and (e) sterilizing said medical devicewith ionizing radiation selected from the group consisting of gammaradiation, E-beam radiation, x-ray radiation, and combinations thereofat a dose of between about 0.1 kGy and about 0.3 kGy; wherein themedical device is effective for its intended use following sterilizationwith radiation.
 2. The method of claim 1, wherein the at least oneradiosensitizer is selected from the group consisting of psoralen andits derivatives and analogs; inactines and their derivatives andanalogs; angelicins; khellins; coumarins; nucleic acid bindingcompounds; brominated hematoporphyrin; phthalocyanines; purpurins;porphyrins; halogenated or metal atom-substituted derivatives ofdihematoporphyrin esters, hematoporphyrin derivatives, benzoporphyrinderivatives, hydrodibenzoporphyrin dimaleimade, hydrodibenzoporphyrin,dicyano disulfone, tetracarbethoxy hydrodibenzoporphyrin, andtetracarbethoxy hydrodibenzoporphyrin dipropionamide; doxorubicin;daunomycin; netropsin; BD peptide, S2 peptide; S-303 (ALE compound);hypericin, methylene blue, toluidine blue, eosin, fluoresceins, flavins,merocyanine 540; bergapten; and SE peptide.
 3. The method of claim 1,wherein the at least one radiosensitizer is methylene blue present in anamount of from about 20 μg/mL to about 75 μg/mL.
 4. The method of claim1, wherein the at least one radiosensitizer is riboflavin present in anamount of from about 200 μg/mL to about 5 mg/mL.
 5. The method of claim1, wherein the polymeric material comprises a polymer selected from thegroup consisting of poly(lactide), poly(glycolide), poly(dioxanone),poly(ε-caprolactone), poly(hydroxybutyrate), poly(β-hydroxybutyrate),poly(hydroxyvalerate), poly(tetramethyl carbonate),poly(lactide-co-glycolide), poly(amino acids) and copolymers andterpolymers thereof.
 6. The method of claim 1, wherein the polymericmaterial comprises a proteinaceous polymer selected from the groupconsisting of alginate, albumins, algal proteins, apoproteins, lectins,lipoproteins, metalloproteins, polyproteins, collagen, elastin,fibronectins, laminin, tenascin, vitronectin, fibroin, gelatin, keratin,reticulin, poly(alpha-amino acid), poly(beta-amino acid),poly(gamma-amino acid), polyimino acid, polypeptide and derivativesthereof.
 7. The method of claim 1, wherein the radiosensitizer ismethylene blue and the polymeric material comprises gelatin.
 8. Themethod of claim 1, wherein the radiosensitizer is riboflavin and thepolymeric material comprises gelatin.